Age-related non-traumatic fractures are a major public health problem. Even though lower bone mass is the most commonly implicated variable for the age-related increase in fracture incidence, studies show that the resistance of bone material against fracture (toughness) diminishes with age. The mechanisms for the age related loss of toughness are, however, unknown. Collagen deformation and microcrack formation during fracture are the primary mechanisms of toughening in bone and preliminary studies demonstrate that nonenzymatically (NEG) mediated accumulation of crosslinks in bone collagen stiffen the organic network and reduced collagen deformation and microcracking in bone. The NEG mediated stiffening of the organic matrix may, therefore, cause the age-related loss of toughness. Furthermore, as post-yield and damage behaviors of cancellous bone are independent of the bone volume fraction and similar to that of cortical bone, the organic matrix mediated loss of toughening mechanisms may be common to both cortical and cancellous bones. The overall goal of this study is to investigate the effects of NEG-mediated collagen crosslinks on the age-related increase in cortical and cancellous bone fragility. The project will use in vitro ribosylation, mechanical testing and microdamage assessment of normal and glycated as well mineralized and demineralized human cortical and cancellous bones to determine whether: (H1) Age related accumulation of NEG products in bone collagen is associated with an increased organic matrix stiffness, reduced magnitude of toughening mechanisms and decreased crack propagation resistance;(H2) In vitro ribosylation causes similar modifications in the collagen crosslinks, organic matrix stiffness, toughening mechanisms and crack propagation resistance of human bone as are observed in vivo;and (H3) Age-related changes in the NEG content, post-yield properties, organic matrix stiffness and toughening mechanisms are similar for both cortical and cancellous bones. This project will: (a) improve the prediction of fracture risk by providing NEG-mediated collagen crosslinks as a new measure of bone quality;(b) provide a basis for a pharmaceutical technique to improve bone quality;(c) improve the understanding of fractures in diabetics.